Cinnamomeoventrolide – Double-bond Regioisomerism in Frog Semiochemcials

Abstract Frogs of the families Mantellinae and Hyperoliidae possess male specific femoral or gular glands that are used during courtship. These glands release volatile compounds, e. g. the macrocyclic lactone gephyromantolide A (2,6,10-trimethyl-6-undecen-11-olide) in the case of Gephyromantis boulengeri (Mantellinae). During the analysis of the volatiles of Hyperolius cinnamomeoventris (Hyperoliidae) we detected a compound A showing high similarity with the spectrum of gephyromantolide A. Nevertheless, the slight differences led to the proposal of a regioisomer as a structure for A, 2,6,10-trimethyl-5-undecen-11-olide that we called cinnamomeoventrolide. To proof our proposal, a versatile synthesis was developed that allowed access to all four stereoisomers from a single chiral starting material, the so-called (S)-Roche ester, using ring-closing metathesis as a key step. With these stereoisomers the absolute configuration of the natural product was established to have the (2R,10S)-configuration by GC on a chiral phase. The configuration of natural gephyromantolide A is the opposite. Both frogs seem to use a similar biosynthetic pathway to the target compounds, differing in the stereochemistry of the reduction step, and requiring an additional isomerization in case of G. boulengeri. The unique regioisomer differentiation of double bonds has so far only been reported from insects. The compounds are likely to play a role in species-recognition of the frogs.